a) Field of the Invention
This invention relates to 8-(oxo-substituted cycloalkyl)xanthines and pharmaceutically acceptable salts thereof which possess useful and relatively potent and selective bronchodilating and cardiotonic activity. The compounds can reverse histamine-induced bronchoconstriction in guinea pigs and protect against pentobarbital-induced heart failure in rats.
b) State of the Art
Many xanthine derivatives, as exemplified by theophylline and caffeine, induce a variety of pharmacological effects, including antiasthmatic, diuretic, respiratory stimulant, central stimulant, cardiac stimulant, and analgetic adjuvant activities [J. W. Daly, J. Med. Chem. 25, 197-207 (1982)]. The central nervous system (CNS) stimulating effects of these agents include the production of nervousness, restlessness, insomnia, tremors, hyperesthesia, and other signs of CNS stimulation. At high doses they may even cause convulsions and seizures. Xanthines also activate the medullary respiratory centers where the drugs appear to increase the sensitivity of these centers to the stimulatory actions of carbon dioxide.
The xanthines also have prominent actions on the circulatory system. For example, theophylline produces modest decreases in peripheral vascular resistance, sometimes powerful cardiac stimulation, and increased perfusion of most organs that may result in diuresis. Moreover, another agent, amrinone, which is related to xanthines, is a widely used effective cardiotonic agent [A. W. Ward, R. N. Brogden, R. C. Heel, T. M. Speight and G. S. Avery, Drugs 26, 468-502 (1983); L. N. Seigel et al., Am. Heart J. 106, 1042-1047 (1983)].
A disadvantage of the use of theophylline in patients with compromised circulatory function is that it frequently causes CNS and cardiac toxicity [K. M. Piafsky, S. D. Sitar, R. E. Rango, and R. I. Ogiline, Clin. Pharmacol. Ther. 21, 310-316 (1977)]. As a result more effective vasodilators, specific inotropic agents and diuretics now find favor in clinical practice [J. N. Cohn and J. A. Franciosa, N. Engl. J. Med. 297, 254-258 (1977)]. At therapeutic doses theophylline causes modest increases in heart rate and decreases in peripheral vascular resistance, thus resulting in an increased blood flow; however, in man this effect is short-lived.
Many xanthines also cause relaxation of a variety of smooth muscles, especially smooth muscle of the bronchi which has been constricted experimentally by histamine or clinically in asthma. Theophylline is of value in the treatment of bronchial asthma where it produces a demonstrable increase in vital capacity. The effects of theophylline on the cardiovascular system and CNS, together with a narrow therapeutic window, however, reduce the effectiveness of its therapeutic utility.
The xanthines produce a number of other pharmacological effects in addition to the aforementioned ones. For example, they may increase skeletal muscle tone, an effect possibly involving Ca.sup.2 + translocation. Moreover, xanthines have been shown to augment release of secretory products by various endocrine and exocrine tissues, whereas they have been shown to inhibit the secretion of mediators of inflammation by mast cells and other tissues.
Such diverse pharmacological effects of xanthines have been attributed to three basic cellular actions: (1) mechanisms associated with translocation of intracellular calcium, (2) effects mediated by increasing accumulation of cyclic nucleotides and (3) effects mediated by blockade of adenosine receptors [See, e.g., T. W. Rall in "Goodman and Gilman's The Pharmacological "Basis of Therapeutics", 7th Ed., A. G. Gilman, L. S. Goodman, T. W. Rall, and F. Murad, eds., MacMillan, N.Y., 1985, pp. 589-603)]. The third mechanism has received greatest attention recently; i.e., that xanthines exert their pharmacological effects primarily as adenosine receptor antagonists. There are at least two subpopulations of such receptors, designated A:, which inhibit adenylate cyclase, and A.sub.2, which stimulate adenylate cyclase [See, e.g., R. F. Bruns, J. W. Daly and S. H. Snyder, Proc. Natl. Acad. Sci. U.S.A. 80, 2077-2080 (1983)]. Receptor binding studies have indicated receptor heterogeneity among the A.sub.1 subtype [K. M. Murphy and S. H. Snyder, Mol. Pharmacol. 22, 250-257 (1982)] as well as different tissue distributions for the receptor subtypes.
Whereas, certain xanthine derivatives demonstrate receptor selectivity, caffeine and theophylline are about equally effective in displacing ligands from both the A.sub.1 and A.sub.2 adenosine receptors. It is uncertain, however, whether therapeutic responses to theophylline administration in asthmatic patients involve antagonism of adenosine receptors. This uncertainty is based largely on the observation that enprofylline (3-propylxanthine), an agent that appears to be about five-fold more potent than theophylline as a bronchodilator in man and other species [C. G. A. Persson, Agents Actions 13 (Suppl.), 115-129 (1983)], is much less effective than theophylline in diminishing responses to adenosine in all tissues studied, except for the rat hippocampus [B. B. Fredholm and C. G. A. Persson, Eur. J. Pharmacol. 81, 673-676 (1982)].
The present invention provides new, potent and selective xanthines which are effective in reversing histamine-induced bronchoconstriction in guinea pigs and preventing pentobarbital-induced heart failure in rats. These new 1,3-substituted-8-(oxo-substituted cycloalkyl)xanthines have useful bronchodilating and cardiotonic activity.